DOCSLIB.ORG

Sortilin, Sorcs1b, and Sorla Vps10p Sorting Receptors, Are Novel Γ

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Sortilin, Sorcs1b, and Sorla Vps10p Sorting Receptors, Are Novel Γ Molecular Neurodegeneration BioMed Central Research article Open Access Sortilin, SorCS1b, and SorLA Vps10p sorting receptors, are novel γ-secretase substrates Andrew C Nyborg1, ThomasBLadd1, Craig W Zwizinski1, James J Lah2 and Todd E Golde*1 Address: 1Department of Neuroscience, Mayo Clinic Jacksonville, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA and 2Department of Neurology, Center for Neurodegenerative Disease, Emory University, Whitehead Biomedical Research Building, 615 Michael Street, Suite 505, Atlanta, GA 30322, USA Email: Andrew C Nyborg - [email protected]; Thomas B Ladd - [email protected]; Craig W Zwizinski - [email protected]; James J Lah - [email protected]; Todd E Golde* - [email protected] * Corresponding author Published: 12 June 2006 Received: 26 April 2006 Accepted: 12 June 2006 Molecular Neurodegeneration 2006, 1:3 doi:10.1186/1750-1326-1-3 This article is available from: http://www.molecularneurodegeneration.com/content/1/1/3 © 2006 Nyborg et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: The mammalian Vps10p sorting receptor family is a group of 5 type I membrane homologs (Sortilin, SorLA, and SorCS1-3). These receptors bind various cargo proteins via their luminal Vps10p domains and have been shown to mediate a variety of intracellular sorting and trafficking functions. These proteins are highly expressed in the brain. SorLA has been shown to be down regulated in Alzheimer's disease brains, interact with ApoE, and modulate Aβ production. Sortilin has been shown to be part of proNGF mediated death signaling that results from a complex of Sortilin, p75NTR and proNGF. We have investigated and provide evidence for γ-secretase cleavage of this family of proteins. Results: We provide evidence that these receptors are substrates for presenilin dependent γ- secretase cleavage. γ-Secretase cleavage of these sorting receptors is inhibited by γ-secretase inhibitors and does not occur in PS1/PS2 knockout cells. Like most γ-secretase substrates, we find that ectodomain shedding precedes γ-secretase cleavage. The ectodomain cleavage is inhibited by a metalloprotease inhibitor and activated by PMA suggesting that it is mediated by an α-secretase like cleavage. Conclusion: These data indicate that the α- and γ-secretase cleavages of the mammalian Vps10p sorting receptors occur in a fashion analogous to other known γ-secretase substrates, and could possibly regulate the biological functions of these proteins. Background of the amyloid precursor protein (APP) [3] by β-secretase, γ-Secretase is a multi-component protease complex com- γ-secretase cleavage releases the amyloid beta peptide (Aβ) prised of Presenilin (PS) 1 or 2 with Aph-1, Pen-2, and that accumulates in the brains of patients with Alzhe- Nicastrin [1,2] that cleaves type I membrane proteins imer's disease (AD) [4]. γ-Secretase also plays a key role in within their transmembrane domains. γ-Secretase cata- mediating signaling via the Notch receptors [5-7]. In most lyzes a number of important physiological and patho- cases, knockout of presenilin or other components of the physiological cleavages. Following ectodomain cleavage γ-secretase complex produces an embryonic lethal pheno- Page 1 of 11 (page number not for citation purposes) Molecular Neurodegeneration 2006, 1:3 http://www.molecularneurodegeneration.com/content/1/1/3 type, that resembles the phenotype produced by knockout the substrate deleted in colorectal cancer (DCC) attenu- of Notch 1. ates receptor-mediated intracellular signaling pathways that are critical in regulating glutamatergic synaptic trans- To date, more than 25 γ-secretase substrates have been mission and memory processes [18,41]. identified. [8-28]. All identified γ-secretase substrates are type I transmembrane proteins [29] and contain a puta- Because of their topologic similarity to other γ-secretase tive stop transfer sequence immediately following the substrates and evidence for ectodomain shedding [42] transmembrane region [30]. In most cases, ectodomain (Figure 1a), we hypothesized that the mammalian Vps10p shedding precedes intramembrane γ-secretase cleavage containing family of proteins might be γ-secretase sub- [31]. For a growing lists of substrates, γ-secretase cleavage strates. Sortilin, SorLA and SorCS1, 2, and 3 comprise the has been shown to mediate downstream signaling events five identified mammalian Vps10p sorting receptors and [32]. have a number of features in common. First, all are type I membrane proteins (Figure 1b). Second, all contain a Although many proteases preferentially cleave at consen- luminal/extracellular cysteine-rich Vps10p domain sus sequences within the substrate, no consensus homologous to the binding domain of the yeast sorting sequence for cleavage by γ-secretase has been identified. γ- receptor for carboxypeptidase Y. Third, all contain a puta- Secretase cleavage always occurs within a putative hydro- tive furin cleavage site. SorCS1-3 and SorLA also contain phobic transmembrane region, but a variety of different additional extracellular domains thought to be involved sites are cleaved even in a single substrate. Alignment of γ- in ligand binding (Figure 1b). Sortilin is also known as secretase substrate transmembrane domains provides lit- neurotensin receptor 3 or gp95, and SorLA is often called tle insight into the sequence requirements for proteolysis LR11. These receptors are hypothesized to have pleio- to occur (Figure 1a) [33]. Likewise mutations of cleavage tropic functions in chaperoning and targeting various car- sites have provided little definitive information on the goes bound to their luminal Vps10p domains between nature of the cleavage, though several models have been various intracellular organelles [43,44]. proposed [34]. These sorting receptors are expressed at high levels in the Following ectodomain shedding, γ-secretase cleavage lib- CNS and in neurons [44-46]. Sortilin is part of the erates both the cytoplasmic fragment and a small secreted machinery that governs cell survival in developing neuro- peptide. For several substrates the liberated cytoplasmic nal tissue and a key determinant in the induction of post- domain has been shown to translocate to the nucleus traumatic neuronal apoptosis [47]. It also mediates rapid where it is involved in nuclear signaling (Notch ErbB4, endocytosis of lipoprotein lipase [48], neurotensin [49], Delta-1 Jagged, APLP1/2). This process is more generally and the proform of nerve growth factor [47]. Sortilin has referred to as regulated intramembrane proteolysis (RIP). been shown to target proteins in the Golgi for transport to RIP of Notch has been intensively studied. Ligand binding late endosomes. Of its many sorting and signaling func- to the Notch extracellular domain results in ectodomain tions, Sortilin was shown to play a role in p75NTR "death cleavage, which is then followed by γ-secretase cleavage. signaling". The cell death signal is a result of a complex of Once liberated the notch intracellular domain (NICD) p75NTR, Sortilin and the precursor form of nerve growth translocates to the nucleus where it binds to CSL family of factor (proNGF) [47] or pro brain-derived neurotrophic transcription factors [35,36]. Notch binding to CSL has factor [50]. been shown to convert CSL from a transcriptional repres- sor to a transcriptional activator [5]. Analogously nuclear Recent data have suggested a role for SorLA in AD. SorLA signaling of the CD44 [37,38] and N-cadherin [39] cyto- was shown to be a receptor for, and interact with, ApoE plasmic domains following γ-secretase cleavage is indi- [51-54]. In addition, it is reduced in AD brains versus age rectly achieved through CBP (CREB-binding protein) matched controls, interacts with APP [55] and regulates activation or suppression, respectively. In some cases Aβ production [56,57]. nuclear translocation of the cytoplasmic domain is not required for signaling following γ-secretase cleavage we provide evidence that Sortilin, SorCS1b and SorLA are [8,13,14,40]. Not all γ-secretase substrates appear to sequentially cleaved by an α-secretase like activity fol- undergo RIP, as ligand binding is not necessary for the ini- lowed by γ-secretase. α-Secretase cleavage results in secre- tiation of cleavage. For example, APP does not appear to tion of a large extracellular domain of the Vps10p require ligand association in order to initiate ectodomain substrates and γ-secretase liberates a COOH-terminal frag- shedding which occurs prior to γ-secretase cleavage. ment (CTF) from the membrane. These data extend very recent studies demonstrating that Sortilin, SorCS1, In most cases, signaling initiated by γ-secretase cleavage SorCS2, SorCS3, and SorLA undergo ectodomain shed- appears to be an activation event. However, cleavage of Page 2 of 11 (page number not for citation purposes) Molecular Neurodegeneration 2006, 1:3 http://www.molecularneurodegeneration.com/content/1/1/3 a b SchematicsFigure 1 of γ-secretase substrates and the mammalian Vps10p proteins Schematics of γ-secretase substrates and the mammalian Vps10p proteins. a) Alignment of the transmembrane domains and juxtamembrane region of known γ-secretase substrates The number of additional amino acids in the cytoplasmic
Load more

Recommended publications
  • The Effects of P75 and Sorcs2 on Neuronal Function and Structure
    The Effects of Zn2+ on the Binding of the BDNF Prodomain with SorCS2 on Neuronal Function and Structure: Implications for Learning and Memory Caroline Pennacchio Briarcliff High School http://www.newscientist.com/data/images/ns/cms/teaser/blog/201211/f0049969_lead.jpg Introduction • Neurons -> Brain • Hippocampus = Control Center • Neural connections -> Brain-Derived Neurotrophic Factor (BDNF) Introduction Review of Literature Research Questions/Hypotheses Methods Bibliography Ligands • Regulate cell proliferation, differentiation • Axon and dendrite growth, synaptogenesis, and synaptic function and plasticity (Reichardt, 2006, Lu, B, Pang, PT, Woo. N.H., 2005, Minichiello L, 2009) http://www.mdpi.com/ijms/ijms-13-13713/article_deploy/html/images/ijms-13-13713f1-1024.png Introduction Review of Literature Research Questions/Hypotheses Methods Bibliography Pro-Neurotrophins • Proteolytically cleaved in trans-Golgi by furin or in secretory granules by pro-protein contervases ] • Extracellular cleavages created in mature domain formation show how to control synaptic functions of neurotrophins (Lu, 2003) • proBDNF regulates hippocampal structure, synaptic transmission, and plasticity (Yang et al., 2014) https://www.researchgate.net/profile/Jay_Pundavela/publication/269520194/figure/fig1/Fig-1-Binding-of-neurotrophins- • Induce apoptotic signaling (Nykjaer et al. 2004; Teng et al. 2005; Jansen et al. and-proneurotrophins-to-Trk-receptors-and-p75NTR-NGF_small.png 2007; Willnow et al. 2008; Yano et al. 2009) Introduction Review of Literature
    [Show full text]
  • Sorcs2 Deletion Leads to Altered Neuronal Lysosome Activity
    bioRxiv preprint doi: https://doi.org/10.1101/2021.04.08.439000; this version posted April 10, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 SorCS2 deletion leads to altered neuronal lysosome activity 2 3 Sérgio Almeida1*, André M. Miranda2, Andrea E. Tóth1, Morten S. Nielsen1 and Tiago Gil Oliveira2 4 1 Department of Biomedicine, Aarhus University, Aarhus, Denmark 5 2 Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal 6 *Corresponding author: Sérgio Almeida, Department of Biomedicine, Aarhus University, Høegh- 7 Guldbergsgade 10, DK-8000C Aarhus, Denmark. Phone: +45 60511406. E-mail: [email protected] 8 9 10 11 12 13 Abstract 14 Vps10p domain receptors are important for regulating intracellular protein sorting within the central 15 nervous system and as such constitute risk factors for different brain pathologies. Here, we show that 16 removal of SorCS2 leads to altered lysosomal activity in mouse primary neurons. SorCS2-/- neurons show 17 elevated lysosomal markers such as LAMP1 and acidic hydrolases including cathepsin B and D. Despite 18 increased levels, SorCS2-/- neurons fail to degrade cathepsin specific substrates in a live context. SorCS2- 19 deficient mice present an increase in lysolipids, which may contribute to membrane permeabilization and 20 increased susceptibility to lysosomal stress. Our findings highlight SorCS2 as an important factor for a 21 balanced neuronal lysosome milieu.
    [Show full text]
  • Recent Efforts to Dissect the Genetic Basis of Alcohol Use and Abuse
    Title: Recent efforts to dissect the genetic basis of alcohol use and abuse Authors: Sandra Sanchez-Roige, PhD1, Abraham A. Palmer, PhD1,2, Toni-Kim Clarke, PhD3 Affiliations: 1 Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093, USA, 2 Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, 92093, USA, 3 Division of Psychiatry, University of Edinburgh, Edinburgh, UK Correspondence: Sandra Sanchez-Roige, Ph.D. Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093, USA. E-mail: [email protected] Short Title: Alcohol genetics Keywords: alcoholism; alcohol consumption; AUDIT; alcohol-metabolizing genes; Genome- wide association studies; Genetics Word count: 3,981 1 Abstract (202 words) Alcohol use disorders (AUD) are defined by several symptom criteria, which can be further dissected at the genetic level. Over the past several years, our understanding of the genetic factors influencing alcohol use and abuse has progressed tremendously; hundreds of loci have now been implicated in different aspects of alcohol use. Previously known associations with alcohol metabolizing enzymes (ADH1B, ALDH2) have been definitively replicated. Additionally, novel associations with loci containing the genes KLB, GCKR, CRHR1 and CADM2 have been reported. Downstream analyses have leveraged these genetic findings to reveal important relationships between alcohol use behaviors and both physical and mental health. AUD and aspects of alcohol misuse have been shown to overlap strongly with psychiatric disorders, whereas aspects of alcohol consumption have shown stronger links to metabolism. These results demonstrate that the genetic architecture of alcohol consumption only partially overlaps with the genetics of clinically defined AUD.
    [Show full text]
  • Mood Stabilizers in Psychiatric Disorders and Mechanisms Learnt from in Vitro Model Systems
    International Journal of Molecular Sciences Review Mood Stabilizers in Psychiatric Disorders and Mechanisms Learnt from In Vitro Model Systems Ritu Nayak, Idan Rosh, Irina Kustanovich and Shani Stern * Sagol Department of Neurobiology, University of Haifa, Haifa 3498838, Israel; [email protected] (R.N.); [email protected] (I.R.); [email protected] (I.K.) * Correspondence: [email protected] Abstract: Bipolar disorder (BD) and schizophrenia are psychiatric disorders that manifest unusual mental, behavioral, and emotional patterns leading to suffering and disability. These disorders span heterogeneous conditions with variable heredity and elusive pathophysiology. Mood stabilizers such as lithium and valproic acid (VPA) have been shown to be effective in BD and, to some extent in schizophrenia. This review highlights the efficacy of lithium and VPA treatment in several randomized, controlled human trials conducted in patients suffering from BD and schizophrenia. Furthermore, we also address the importance of using induced pluripotent stem cells (iPSCs) as a disease model for mirroring the disease’s phenotypes. In BD, iPSC-derived neurons enabled finding an endophenotype of hyperexcitability with increased hyperpolarizations. Some of the disease phenotypes were significantly alleviated by lithium treatment. VPA studies have also reported rescuing the Wnt/β-catenin pathway and reducing activity. Another significant contribution of iPSC models can be attributed to studying the molecular etiologies of schizophrenia such as abnormal differentiation of patient-derived neural stem cells, decreased neuronal connectivity and neurite Citation: Nayak, R.; Rosh, I.; number, impaired synaptic function, and altered gene expression patterns. Overall, despite significant Kustanovich, I.; Stern, S. Mood advances using these novel models, much more work remains to fully understand the mechanisms Stabilizers in Psychiatric Disorders by which these disorders affect the patients’ brains.
    [Show full text]
  • 14Th Annual OAK Meeting Aarhus 29 May 2015
    14th Annual OAK Meeting Danish Brain Research Laboratories Meeting Aarhus 29 May 2015 Aarhus University Merete Barker Auditorium www.cfin.au.dk/OAK-2015 14th Annual OAK Meeting Danish Brain Research Laboratories Meeting PROGRAM Friday 29 May 2015 10:00 Arrival & registration at Merete Barker Auditorium, Aarhus University 10:15-10:30 Welcome by Arne Møller Session 1: In-vivo Neuroimaging (Chair: Anne M. Landau & Kim Ryun Drasbek) 10:30-10:45 Ali Khalidan Vibholm: Preclinical in-vivo imaging of activated NMDA receptor ion channels with the novel radioligand [18F]-GE179 10:45-11:00 Athanasios Metaxas: PET imaging of the NMDA receptor using [18F]PK209 11:00-11:15 Andreas N. Glud: Parkinson’s disease models of abnormal protein aggregation in the Göttingen minipig CNS 11:15-11:30 Jenny-Ann Phan: Alpha synuclein model of Parkinson’s disease displays early synaptic disruption 11:30-11:45 Janne Vejlby: Endocannabinoid modulation of noradrenaline release 11:45-12:00 Majken Borup Thomsen: Increased receptor density of α2 adrenoceptors and GABAA α5 receptors in limbic brain regions in the domoic acid rat model of epilepsy 12.00-13.00 LUNCH BREAK Session 2: Animal models (Chair: Flemming Fryd Johansen) 13:00-13:15 Charlotte Havelund Nykjær: Stereological estimation of the brain white matter in Multiple System Atrophy 13:15-13:30 Jonas Folke: Deregulation of Wnt pathway in the prefrontal cortex from Alzheimer’s disease brains 13:30-13:45 Anders Malmendal: Insights into Alzheimer’s disease from NMR metabolomics of Aβ-expressing Drosophila 13:45-14:00
    [Show full text]
  • Independent and Epistatic Effects of Variants in VPS10-D Receptors on Alzheimer Disease Risk and Processing of the Amyloid Precursor Protein (APP)
    Citation: Transl Psychiatry (2013) 3, e256; doi:10.1038/tp.2013.13 & 2013 Macmillan Publishers Limited All rights reserved 2158-3188/13 www.nature.com/tp Independent and epistatic effects of variants in VPS10-d receptors on Alzheimer disease risk and processing of the amyloid precursor protein (APP) C Reitz1,2,3, G Tosto2, B Vardarajan4, E Rogaeva5, M Ghani5, RS Rogers2, C Conrad2, JL Haines6, MA Pericak-Vance7, MD Fallin8, T Foroud9, LA Farrer4,10,11,12,13,14, GD Schellenberg15, PS George-Hyslop5,16,17, R Mayeux1,2,3,18,19,20 and the Alzheimer’s Disease Genetics Consortium (ADGC) Genetic variants in the sortilin-related receptor (SORL1) and the sortilin-related vacuolar protein sorting 10 (VPS10) domain- containing receptor 1 (SORCS1) are associated with increased risk of Alzheimer’s disease (AD), declining cognitive function and altered amyloid precursor protein (APP) processing. We explored whether other members of the (VPS10) domain-containing receptor protein family (the sortilin-related VPS10 domain-containing receptors 2 and 3 (SORCS2 and SORCS3) and sortilin (SORT1)) would have similar effects either independently or together. We conducted the analyses in a large Caucasian case control data set (n ¼ 11 840 cases, 10 931 controls) to determine the associations between single nucleotide polymorphisms (SNPs) in all the five homologous genes and AD risk. Evidence for interactions between SNPs in the five VPS10 domain receptor family genes was determined in epistatic statistical models. We also compared expression levels of SORCS2, SORCS3 and SORT1 in AD and control brains using microarray gene expression analyses and assessed the effects of these genes on c-secretase processing of APP.
    [Show full text]
  • Sorcs2-Mediated NR2A Trafficking Regulates Motor Deficits in Huntington’S Disease
    SorCS2-mediated NR2A trafficking regulates motor deficits in Huntington’s disease Qian Ma, … , Lino Tessarollo, Barbara L. Hempstead JCI Insight. 2017;2(9):e88995. https://doi.org/10.1172/jci.insight.88995. Research Article Neuroscience Motor dysfunction is a prominent and disabling feature of Huntington’s disease (HD), but the molecular mechanisms that dictate its onset and progression are unknown. The N-methyl-D-aspartate receptor 2A (NR2A) subunit regulates motor skill development and synaptic plasticity in medium spiny neurons (MSNs) of the striatum, cells that are most severely impacted by HD. Here, we document reduced NR2A receptor subunits on the dendritic membranes and at the synapses of MSNs in zQ175 mice that model HD. We identify that SorCS2, a vacuolar protein sorting 10 protein–domain (VPS10P- domain) receptor, interacts with VPS35, a core component of retromer, thereby regulating surface trafficking of NR2A in MSNs. In the zQ175 striatum, SorCS2 is markedly decreased in an age- and allele-dependent manner. Notably, SorCS2 selectively interacts with mutant huntingtin (mtHTT), but not WT huntingtin (wtHTT), and is mislocalized to perinuclear clusters in striatal neurons of human HD patients and zQ175 mice. Genetic deficiency of SorCS2 accelerates the onset and exacerbates the motor coordination deficit of zQ175 mice. Together, our results identify SorCS2 as an interacting protein of mtHTT and demonstrate that impaired SorCS2-mediated NR2A subunit trafficking to dendritic surface of MSNs is, to our knowledge, a novel mechanism contributing to motor coordination deficits of HD. Find the latest version: https://jci.me/88995/pdf RESEARCH ARTICLE SorCS2-mediated NR2A trafficking regulates motor deficits in Huntington’s disease Qian Ma,1 Jianmin Yang,2,3 Teresa A.
    [Show full text]
  • Large-Scale Interaction Effects Reveal Missing Heritability in Schizophrenia, Bipolar Disorder and Posttraumatic Stress Disorder
    OPEN Citation: Transl Psychiatry (2017) 7, e1089; doi:10.1038/tp.2017.61 www.nature.com/tp ORIGINAL ARTICLE Large-scale interaction effects reveal missing heritability in schizophrenia, bipolar disorder and posttraumatic stress disorder HJ Woo, C Yu, K Kumar and J Reifman Genetic susceptibility factors behind psychiatric disorders typically contribute small effects individually. A possible explanation for the missing heritability is that the effects of common variants are not only polygenic but also non-additive, appearing only when interactions within large groups are taken into account. Here, we tested this hypothesis for schizophrenia (SZ) and bipolar disorder (BP) disease risks, and identified genetic factors shared with posttraumatic stress disorder (PTSD). When considered independently, few single-nucleotide polymorphisms (SNPs) reached genome-wide significance. In contrast, when SNPs were selected in groups (containing up to thousands each) and the collective effects of all interactions were estimated, the association strength for SZ/BP rose dramatically with a combined sample size of 7187 cases and 8309 controls. We identified a large number of genes and pathways whose association was significant only when interaction effects were included. The gene with highest association was CSMD1, which encodes a negative regulator of complement activation. Pathways for glycosaminoglycan (GAG) synthesis exhibited strong association in multiple contexts. Taken together, highly associated pathways suggested a pathogenesis mechanism where maternal immune activation causes disruption of neurogenesis (compounded by impaired cell cycle, DNA repair and neuronal migration) and deficits in cortical interneurons, leading to symptoms triggered by synaptic pruning. Increased risks arise from GAG deficiencies causing complement activation and excessive microglial action.
    [Show full text]
  • View Full Page
    14080 • The Journal of Neuroscience, October 10, 2012 • 32(41):14080–14086 Symposium Vps10 Family Proteins and the Retromer Complex in Aging-Related Neurodegeneration and Diabetes Rachel F. Lane,1 Peter St George-Hyslop,2,3 Barbara L. Hempstead,4 Scott A. Small,5 Stephen M. Strittmatter,6 and Sam Gandy7,8 1Alzheimer’s Drug Discovery Foundation, New York, New York 10019, 2Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON M5S 3H2 Canada, 3Cambridge Institute for Medical Research and Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0XY, United Kingdom, 4Department of Medicine, Weill Cornell Medical College, New York, New York 10065, 5Department of Neurology and the Taub Institute, Columbia University, School of Physicians and Surgeons, New York, New York 10032, 6Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06536, 7Departments of Neurology and Psychiatry and the Alzheimer’s Disease Research Center, Mount Sinai School of Medicine, New York New York 10029, and 8James J. Peters Veterans Affairs Medical Center, Bronx, New York 10468 Members of the vacuolar protein sorting 10 (Vps10) family of receptors (including sortilin, SorL1, SorCS1, SorCS2, and SorCS3) play pleiotropic functions in protein trafficking and intracellular and intercellular signaling in neuronal and non-neuronal cells. Interactions have been documented between Vps10 family members and the retromer
    [Show full text]
  • Sorcs2 Controls Functional Expression of Amino Acid Transporter EAAT3 to Protect Neurons from Oxidative Stress and Epilepsy-Induced Pathology
    bioRxiv preprint doi: https://doi.org/10.1101/426734; this version posted September 25, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. SorCS2 controls functional expression of amino acid transporter EAAT3 to protect neurons from oxidative stress and epilepsy-induced pathology Anna R. Malik* (1), Kinga Szydlowska (2), Karolina Nizinska (2), Antonino Asaro (1), Erwin A. van Vliet (3, 4), Oliver Popp (1), Gunnar Dittmar (5), Anders Nykjaer (6) Katarzyna Lukasiuk (2), Eleonora Aronica (3, 7), Thomas E. Willnow*,# (1) 1. Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany 2. Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland 3. Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands 4. Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH, Amsterdam, The Netherlands 5. Department of Oncology, Luxembourg Institute of Health, 1445 Strassen, Luxembourg 6. MIND Center, Danish Research Institute of Translational Neuroscience - DANDRITE, The Danish Research Foundation Center PROMEMO, Departments of Biomedicine, Aarhus University, and Neurosurgery, Aarhus University Hospital, DK-8000C Aarhus Denmark 7. Stichting Epilepsie Instellingen Nederland (SEIN), 2103 SW Heemstede, The Netherlands # Lead Contact * Correspondence to: Anna R. Malik Max-Delbrueck-Center for Molecular Medicine Robert-Roessle-Str. 10, D-13125 Berlin, Germany Phone: +49-30-9406-3414 Email: [email protected] Thomas E. Willnow Max-Delbrueck-Center for Molecular Medicine Robert-Roessle-Str. 10, D-13125 Berlin, Germany Phone: +49-30-9406-2569 Email: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/426734; this version posted September 25, 2018.
    [Show full text]
  • Putting Cells in Motion: Advantages of Endogenous Boosting of BDNF Production
    cells Commentary Putting Cells in Motion: Advantages of Endogenous Boosting of BDNF Production Elvira Brattico 1,2,* , Leonardo Bonetti 1, Gabriella Ferretti 3, Peter Vuust 1 and Carmela Matrone 3,* 1 Center for Music in the Brain, Department of Clinical Medicine, Aarhus University & The Royal Academy of Music Aarhus/Aalborg, 8000 Aarhus, Denmark; [email protected] (L.B.); [email protected] (P.V.) 2 Department of Education, Psychology, Communication, University of Bari “Aldo Moro”, 70121 Bari, Italy 3 Unit of Pharmacology, Department of Neuroscience, Faculty of Medicine, University of Naples Federico II, via Pansini 5, 80131 Naples, Italy; [email protected] * Correspondence: [email protected] (E.B.); [email protected] (C.M.) Abstract: Motor exercise, such as sport or musical activities, helps with a plethora of diseases by modulating brain functions in neocortical and subcortical regions, resulting in behavioural changes related to mood regulation, well-being, memory, and even cognitive preservation in aging and neurodegenerative diseases. Although evidence is accumulating on the systemic neural mechanisms mediating these brain effects, the specific mechanisms by which exercise acts upon the cellular level are still under investigation. This is particularly the case for music training, a much less studied instance of motor exercise than sport. With regards to sport, consistent neurobiological research has focused on the brain-derived neurotrophic factor (BDNF), an essential player in the central nervous system. BDNF stimulates the growth and differentiation of neurons and synapses. It thrives in the hippocampus, the cortex, and the basal forebrain, which are the areas vital for memory, learning, and higher cognitive functions.
    [Show full text]
  • Sorting Receptor SORLA – a Trafficking Path to Avoid Alzheimer Disease
    ARTICLE SERIES: Cell Biology and Disease Commentary 2751 Sorting receptor SORLA – a trafficking path to avoid Alzheimer disease Thomas E. Willnow1,* and Olav M. Andersen2,* 1Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany 2The Lundbeck Foundation Research Center MIND, Danish Research Institute of Translational Neuroscience Nordic-EMBL Partnership, and Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark. *Authors for correspondence ([email protected]; [email protected]) Journal of Cell Science 126, 2751–2760 ß 2013. Published by The Company of Biologists Ltd doi: 10.1242/jcs.125393 Summary Excessive proteolytic breakdown of the amyloid precursor protein (APP) to neurotoxic amyloid b peptides (Ab) by secretases in the brain is a molecular cause of Alzheimer disease (AD). According to current concepts, the complex route whereby APP moves between the secretory compartment, the cell surface and endosomes to encounter the various secretases determines its processing fate. However, the molecular mechanisms that control the intracellular trafficking of APP in neurons and their contribution to AD remain poorly understood. Here, we describe the functional elucidation of a new sorting receptor SORLA that emerges as a central regulator of trafficking and processing of APP. SORLA interacts with distinct sets of cytosolic adaptors for anterograde and retrograde movement of APP between the trans-Golgi network and early endosomes, thereby restricting delivery of the precursor to endocytic compartments that favor amyloidogenic breakdown. Defects in SORLA and its interacting adaptors result in transport defects and enhanced amyloidogenic processing of APP, and represent important risk factors for AD in patients. As discussed here, these findings uncovered a unique regulatory pathway for the control of neuronal protein transport, and provide clues as to why defects in this pathway cause neurodegenerative disease.
    [Show full text]